When is enough, enough?

With advances in reproductive technologies it seems that there is no shortage of things we can do to (for) infertile couples trying to start or extend their family. Nothing seems to be out of reach anymore. We have an alphabet soup of procedures including IUI, HSGs, L/S and H/S, SOIUI, IVF, ICSI, GIFT, ZIFT, PGD, etc., etc. If a woman doesn’t have eggs, we can get some from someone else. If a man doesn’t have sperm, ditto. Testicular biopsy or epididymal aspiration with intracytoplasmic sperm injection (ICSI) has changed the outcomes for men with azospermia or after vasectomy. Women without a uterus can find a gestational carrier. Serious gene defects can be weeded out and eliminated from the gene pool of the next generation using preimplantation genetic diagnosis (PGD).  The number of things we can do is astounding, but so is the cost.

Living in SC, I’ve felt a reluctance on the part of certain couples to go to the extremes, even to IVF, when other plans don’t pan out. There are concerns about creating life that they won’t be able to nurture and protect. These couples may have the financial ability to make use of our latest miraculous cures, but choose not to go there for other more personal reasons. Even here concessions can be made and explanations given that can ameliorate concerns and provide avenues that are more acceptable, such as freezing oocytes (eggs) instead of fertilizing them with a sperm.

The second group that stops short of taking advantage of the most advanced techniques are those that don’t have health insurance, or have insurance without infertility benefits.  Financial capital, like emotional capital is not an infinite resource and boundaries should be discussed so that couples know when enough is enough. When all else fails, there is still adoption, which also can be very expensive.  Donor egg cycles continue to excalate in price as donors get more and more for donating their eggs. Keeping resources set aside  for this choice is an important consideration as well.

Finally, there are those that have done it all and still are not pregnant. Sometimes, these couples have skipped a step along the way, heading straight to IVF and IVF hasn’t worked. My first patient that I diagnosed with implantation failure and endometriosis had spent her $25K of insurance on 3 IVF but had never had a laparoscopy. She now has three beautiful children after laparoscopy found and treated her underlying problem and she was able to conceive naturally. Fast forward 20 years and its still happening (http://www.ghsumc.org/FertilityCenter/wilmas_story.htm). Even so, we see couples occasionally who baffle the experts and have no known reason for their infertility. They’ve submitted their bodies to all available tests and procedures and still don’t conceive. Nothing seems to work. There comes a time in the relationship when I know its time to stop. Being an optimist, I find it hard to admit defeat. Still, it is our duty to our patients to recognize in them when it is time to stop trying or to take a break. Sometimes they agree and sometimes they don’t. A second opinion is always OK to recommend as well.

I hope that all patients with infertility seeing specialists can maintain some control over their journey through infertility and have the type of relationship with their doctor where they can have this discussion, if necessary. Not everyone gets pregnant but everyone should be allowed to stop, even when enough is not  enough.

Secondary Infertility

Primary infertility is difficulty establishing a pregnancy after 1 year of unprotected intercourse. Secondary infertility is difficulty getting pregnant after having been pregnancy in the past. There is some disagreement about this term; I like to use it for couples that have had a successful pregnancy in the past, since repeated losses or even a single miscarriage in the past doesn’t connote fertility, at least to me. Also, I tend to think about secondary infertility as primary infertility if the first pregnancy was in the distant past.

In many ways the work up for secondary infertility is similar to that of primary infertility (see Infertility Workup 101).  In cases where couples have been successful before at establishing a pregnancy, we often ask “what has changed”?  Is the partner the same one from before?  Did the woman have surgery or illness since the last pregnancy? Did anything happen in childbirth that might have altered the woman’s fertility? Did the patient gain or lose weight?  If the first pregnancy occurred only after many months, there may have been a problem that is antecedent to the first pregnancy. 

Some common findings are a decreased sperm count or motility  in the male partner.  Sperm can deteriorate with age or the male partner may have developed prostatitis or other infections or been exposed to environmental toxins. Weight gain in the male partner can lead to poor sperm counts.

In women who breast feed their baby, activation of a prolactin secreting pituitary adenoma may occur. I’ve seen pituitary tumors result in secondary infertility (see this blog for hyperprolactinemia). Hyper and hypothyroidism can develop between pregnancies. A Cesarean section (C-section) might rarely cause intrauterine scarring or adenomyosis. Fibroids can develop over time and definitely enlarge during pregnancy. Pregnancy can result in Asherman’s syndrome (scarring of the uterine cavity) especially if the woman had a dilation and curettage (D&C).  Ovulation might be sub-optimal after pregnancy since it sometimes takes awhile to reestablish menstrual cyclicity. In cases where uterine hemorrhage occurred during delivery, there can be pituitary insufficiency (Sheehan’s syndrome).

There are a suprising number of women with secondary infertility who have  endometriosis. This is not a typical diagnosis to find in the previously fertile woman. Often, we find that they conceived quickly after coming off birth control pills (OCPs). The pill can suppress endometriosis so this might make sense. After being off the pill for many months, endometriosis might come back and then cause infertility where  it didn’t have this effect before. Sometimes those same women report being on OCPs because of painful periods as adolescents suggesting they’ve had endometriosis for many years. Its something to consider.

After a careful history and physical exam, the workup for secondary infertility remains:

1. semen analysis
2. laboratory assessment of ovarian reserve (FSH), thyroid (TSH), prolactin, androgenic hormones (testosterone and DHEA-S) measured in the female partner
3. possibly a sonohysterogram or hysterosalpingogram (x-ray or ultrasound of the uterus and/or tubes)
4. consider laparoscopy if the clinical situation warrants it
5. evaluate the cervix and uterus by ultrasound and exam

Approaches to treatment include weight loss and excercise if PCOS is suspected, with possible ovulation induction if needed. Treat any pelvic  problems including fibroids, polyps, retained placenta, ovarian cysts. Treatment of thyroid or prolactin problems is important. Resection of endometriosis if suspected and treatment of male factor infertility (IUI or other assisted reprodutive technologies).  Sometimes empiric management is necessary, including ovulation induction or IVF. Unexplained secondary infertility can be very perplexing but fortunately rate in our hands. 

In general secondary infertility is an interesting and rewarding diagnosis to sort out and treat. It is unclear whether the prevalance is rising but that is our impression.

Society for Gynecologic Investigation – Day 2

SGI = Society for Gynecologic Investigation

Day 2 – March 26th, 2010

Began the morning session with a great talk by Marisa Bartolomei from the University of Pennsylvania on Epigenetics and the Regulation of Genomic Imprinting. Basically, she reviewed how the embryo develops using the instructions from the mother (egg) and father (sperm) and how these instructions are prepared are preserved through methylation of specific gene promoter regions. The sperm and the egg get these specific set of instructions that must be followed during their production. Since these gametes are made in a body that has already undergone development, the egg and sperm producing cells much undergo reprogramming.  Disorders of imprinting (reprogramming) were also discussed, including Beckwith Wiedermann Syndrome which occurs when paternal genes  are released from this methylation based inhibition leading to an overgrowth of the fetus along with other anomalies.

“Adventures in Science: The Joy and Tribulations of a Gynecologist” was presented by Gautam Chaudhuri, an inspirational clinician-scientist who performed pioneering work on the communication of the endothelium (cells lining blood vessels) to the blood vessel wall through nitric oxide (NO). He provided an upbeat summary of an inspired career trying to balance clinical and scientific pursuits.

Other highlights from todays meeting included a presentation by Nanette Rollene from the Mayo Clinic found for the first time that migraines are associated with ovarian hyperstimulation syndrome, a dangerous condition affecting women who receive hyperstimulation for infertility using gonadotropins. This important observation will help us understand both OHSS and migraine better.

The following study by Achache and colleagues reported on a very interesting aspect of implantation of the embryo. The molecule LPA3 appears essential for implantation. The mechanism for it appears to involve binding to the embryo and turning on a cascade of events that includes loosening the cell-cell attachments of the endometrium so that the embryo can gain access to the endometrial stroma. LPA3 knock out mice have an implantation failure.

There was a minisymposium on Endometriosis, with 4 talks: Linda Giudice MD PhD spoke on diagnostic challenges for a non-surgical test for endometriosis. Kevin Osteen spoke on the role of the mouse model using human xenograft tissues. Interestingly, the addition of human white blood cells to these mice limit the growth of the xenografted tissue (endometriotic implants). Dr. Rob Taylor reviewed cytokines and the inflammatory response to endometriosis with a focus on therapeutic targets including novel approaches using herbs. Dr. Serdar Bulun finished the session with a talk about steroidogenic potential of endometriosis and the progesterone resistance mechanism that exist in this disease.

Infertility and Route of Delivery

Pregnancy is supposed to be good for fertility problems, especially endometriosis. Over the years I’ve noticed that women with endometriosis who have been successful at getting pregnant who had C-sections seem to come back to us for continued infertility problems more than those that have vaginal deliveries.

Endometriosis is a condition where endometrial cells (see glossary) are found outside of the uterine cavity. Retrograde menstruation (menstruating backwards out the tubes) is common in most women, but excessive dumping of menstrual debris into the pelvis, over time, may predispose to endometriosis. Women at risk for endometriosis are those with frequent or heavy menses, women with cervical stenosis (narrowing opening of the cervix), or women with congenital problems that makes it more difficult to get blood out of the uterus at the time of menstrual bleeding. Other causes are genetic, and in many cases we just don’t know the cause.  Perhaps performing operations on the cervix for abnormal pap smears (leeps, cold knife cones, cryotherapy) could contribute to cervical stenosis. A vaginal delivery, on the other hand, may open the cervix up and make it more likely for menstrual blood to leave the uterus and not come back. If this is true, it might account for our informal observations that the C-section is just not as good as vaginal delivery.

I’d be interested to hear from anyone who might have more information on this. In the meantime, we’re asking all our successful infertile patients to contact us when they delivery and let us know what route was used.  Over time, we’ll find out which patients are fertile on their own and which come back for more infertility treatments.  It makes sense to me, but to my knowledge no one has studied this question yet.